Volume 3 (2019)

Gold Nanoparticles sensitize pancreatic cancer cells to gemcitabine

Yanyan Huai1, Yushan Zhang1, Xunhao Xiong1, Shamik Das2, Resham Bhattacharya2 and Priyabrata Mukherjee1,2

INTRODUCTION Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease. The mortality rate closely parallels that of incidence [1][2]. The current standard of care for advanced stage PDAC patients includes

Unraveling the molecular principles by which ceramides commit cells to death

Shashank Dadsena1, Dina G. Hassan1 and Joost C.M. Holthuis1

EMERGENCE OF CERAMIDES AS TUMOR SUPPRESSOR LIPIDS Sphingolipids are unusually versatile membrane components that participate in mechanical stability, signaling, and molecular sorting. As the path to their production is paved

Immunosurveillance of cancer cell stress

Seila Lorenzo-Herrero1-3, Christian Sordo-Bahamonde1-3, Segundo González1-3 and Alejandro López-Soto1-3

Cancer development is tightly controlled by effector immune responses that recognize and eliminate malignantly transformed cells. Nonetheless, certain immune subsets, such as tumor-associated macrophages, have been described to promote tumor growth, unraveling a double-edge role of the immune system in cancer. Cell stress can modulate the crosstalk between immune cells and tumor cells, reshaping tumor immunogenicity and/or immune function and phenotype. Infiltrating immune cells are exposed to the challenging conditions typically present in the tumor microenvironment. In return, the myriad of signaling pathways activated in response to stress conditions may tip the balance toward stimulation of antitumor responses or immune-mediated tumor progression. Here, we explore how distinct situations of cellular stress influence innate and adaptive immunity and the consequent impact on cancer establishment and progression.

Myelopoiesis, metabolism and therapy: a crucial crossroads in cancer progression

Antonio Sica1,2, Valentina Guarneri3,4 and Alessandra Gennari5

INTRODUCTION The bone marrow (BM) is a primary lymphoid organ that hosts hematopoietic progenitors and presides over hematopoiesis, which is defined as the production of all types of blood cells.

Impact of prophylactic TNF blockade in the dual PD-1 and CTLA-4 immunotherapy efficacy and toxicity

Maite Alvarez1,2, Itziar Otano1,2, Luna Minute1,2, Maria Carmen Ochoa1,2,3, Elisabeth Perez-Ruiz1,4, Ignacio Melero1,2,3,5,6 and Pedro Berraondo1,2,3

Inhibitory checkpoint blockade (ICB) immunotherapy has produced very significant advances in the fight against cancer (Figure 1). The synergistic combination of PD-1 and CTLA-4 blockade therapy has been successfully used

Immunometabolic cross-talk in the inflamed heart

Federica M. Marelli-Berg1,3 and Dunja Aksentijevic2,3

Inflammatory processes underlie many diseases associated with injury of the heart muscle, including conditions without an obvious inflammatory pathogenic component such as hypertensive and diabetic cardiomyopathy. Persistence of cardiac inflammation can cause irreversible structural and functional deficits. Some are induced by direct damage of the heart muscle by cellular and soluble mediators but also by metabolic adaptations sustained by the inflammatory microenvironment. It is well established that both cardiomyocytes and immune cells undergo metabolic reprogramming in the site of inflammation, which allow them to deal with decreased availability of nutrients and oxygen. However, like in cancer, competition for nutrients and increased production of signalling metabolites such as lactate initiate a metabolic cross-talk between immune cells and cardiomyocytes which, we propose, might tip the balance between resolution of the inflammation versus adverse cardiac remodeling. Here we review our current understanding of the metabolic reprogramming of both heart tissue and immune (...)

The role of epigenetics in hypothalamic energy balance control: implications for obesity

Arnaud Obri1 and Marc Claret1,2

INTRODUCTION The prevalence of obesity continues to increase worldwide. This trend is of concern because of its dramatic economic impact, concomitant decreased lifespan and increased comorbidities, such as hypertension, cardiovascular

Stress and catecholamines modulate the bone marrow microenvironment to promote tumorigenesis

Pauline Hanns1, Anna M. Paczulla1, Michael Medinger2, Martina Konantz1 and Claudia Lengerke1,2

High vascularization and locally secreted factors make the bone marrow (BM) microenvironment particularly hospitable for tumor cells and bones to a preferred metastatic site for disseminated cancer cells of different origins. Cancer cell homing and proliferation in the BM are amongst other regulated by complex interactions with BM niche cells (e.g. osteoblasts, endothelial cells and mesenchymal stromal cells (MSCs)), resident hematopoietic stem and progenitor cells (HSPCs) and pro-angiogenic cytokines leading to enhanced BM microvessel densities during malignant progression. Stress and catecholamine neurotransmitters released in response to activation of the sympathetic nervous system (SNS) reportedly modulate various BM cells and may thereby influence cancer progression. Here we review the role of catecholamines during tumorigenesis with particular focus on pro-tumorigenic effects mediated by the BM niche.

Remodeling of mitochondrial morphology and function: an emerging hallmark of cellular reprogramming

Anuj Rastogi1, Piyush Joshi2,3, Ela Contreras1 and Vivian Gama1,2,3,4

Research in the stem cell field has traditionally focused on understanding key transcriptional factors that provide pluripotent cell identity. However, much less is known about other critical non-transcriptional signaling networks that govern stem cell identity. Although we continue to gain critical insights into the mechanisms underlying mitochondrial morphology and function during cellular reprogramming – the process of reverting the fate of a differentiated cell into a stem cell, many uncertainties remain. Recent studies suggest an emerging landscape in which mitochondrial morphology and function have an active role in maintaining and regulating changes in cell identity. In this review, we will focus on these emerging concepts as crucial modulators of cellular reprogramming. Recognition of the widespread applicability of these concepts will increase our understanding of the mitochondrial mechanisms involved in cell identity, cell fate and disease.

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Stress granules regulate paraspeckles: RNP granule continuum at work

Haiyan An1 and Tatyana A. Shelkovnikova1

Eukaryotic cells contain a variety of large, multicomponent RNA-protein complexes termed ribonucleoprotein (RNP) granules. RNP granules represent membraneless organelles – biomolecular condensates lacking a membrane and maintained through an intricate

Metabolism remodeling in pancreatic ductal adenocarcinoma

Jin-Tao Li1, Yi-Ping Wang1, Miao Yin1 and Qun-Ying Lei1, 2

INTRODUCTION Pancreatic ductal adenocarcinoma (PDAC) is a tumor with early metastatic potential and remarkable resistance to established therapies such as chemotherapy, radiotherapy, and molecular targeted therapy [1]. Given primary localization

LTX-315 – a promising novel antitumor peptide and immunotherapeutic agent

Dagmar Zweytick1,2

Host defense in mammals, as provided by the innate immune system, comprises proteins such as lactoferrin (LF), a multifunctional iron-binding glycoprotein originally discovered in bovine milk. LF is further pepsin-cleaved

Endoplasmic reticulum and Golgi stress in microcephaly

Sandrine Passemard1,2, Franck Perez3, Pierre Gressens1,4 and Vincent El Ghouzzi1

Microcephaly is a neurodevelopmental condition characterized by a small brain size associated with intellectual deficiency in most cases and is one of the most frequent clinical sign encountered in neurodevelopmental disorders. It can result from a wide range of environmental insults occurring during pregnancy or postnatally, as well as from various genetic causes and represents a highly heterogeneous condition. However, several lines of evidence highlight a compromised mode of division of the cortical precursor cells during neurogenesis, affecting neural commitment or survival as one of the common mechanisms leading to a limited production of neurons and associated with the most severe forms of congenital microcephaly. In this context, the emergence of the endoplasmic reticulum (ER) and the Golgi apparatus as key guardians of cellular homeostasis, especially through the regulation of proteostasis, has raised the hypothesis that pathological ER and/or Golgi stress could contribute significantly to cortical impairments eliciting microcephaly. In (…)

LTX-315 sequentially promotes lymphocyte-independent and lymphocyte-dependent antitumor effects

Hsin-Wei Liao1,#, Christopher Garris1,#, Christina Pfirschke1, Steffen Rickelt2, Sean Arlauckas1, Marie Siwicki1, Rainer H. Kohler1, Ralph Weissleder1, Vibeke Sundvold-Gjerstad3, Baldur Sveinbjørnsson3,4, Øystein Rekdal3,4 and Mikael J. Pittet1

LTX-315 is an oncolytic peptide that has antitumor efficacy in mice grafted with various tumor cell lines and is currently being tested in phase II clinical trials. Here we aimed to further evaluate LTX-315 in conditional genetic mouse models of cancer that typically resist current treatment options and to better understand the drug’s mode of action in vivo. We report LTX-315 mediates profound antitumor effects against Braf- and Pten-driven melanoma and delays the progression of Kras- and P53-driven soft tissue sarcoma in mice. Additionally, we show in melanoma that LTX-315 triggers two sequential phases of antitumor response. The first phase of response, which begins within minutes of drug delivery into tumors, is defined by disrupted tumor vasculature and decreased tumor burden and occurs independently of (...)

Anti-regulatory T cells are natural regulatory effector T cells

Niels Ødum 1

It is well established that the immune system uses regulatory immune-suppressive cells to inhibit and terminate immune reactions and maintain immune balance. In the last decade, Andersen and colleagues have

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The role of keratins in modulating carcinogenesis via communication with cells of the immune system

Inês Sequeira1 and Fiona M. Watt1

The connection between inflammation and cancer has been well established; however, little is known about the underlying mechanisms in the context of keratin loss. Keratins belong to a large family

Role of protein phosphatases PP1, PP2A, PP4 and Cdc14 in the DNA damage response

Facundo Ramos1, María Teresa Villoria1, Esmeralda Alonso-Rodríguez1 and Andrés Clemente-Blanco1

INTRODUCTION Cells are constantly suffering endogenous and exogenous stresses that affect the integrity of the genetic material. It has been estimated that every cell of our body is exposed to

Hepatic stress associated with pathologies characterized by disturbed glucose production

Monika Gjorgjieva1-3,#, Gilles Mithieux1-3 and Fabienne Rajas1-3

LIVER FUNCTION IN GLUCOSE PRODUCTION AND NORMOGLYCEMIA Maintaining normal glucose levels in the organism i.e. between 0.7 to 1.1 g/L, is a complex task, involving a multi-organ crosstalk responsible for

Metabolic and functional reprogramming of myeloid-derived suppressor cells and their therapeutic control in glioblastoma

Woong-Jai Won1, Jessy S. Deshane2, Jianmei W. Leavenworth3, Claudia R. Oliva4 and Corinne E. Griguer4

Glioblastoma, also known as glioblastoma multiforme, is the most common and deadliest form of high-grade malignant brain tumors with limited available treatments. Within the glioblastoma tumor microenvironment (TME), tumor cells, stromal cells, and infiltrating immune cells continuously interact and exchange signals through various secreted factors including cytokines, chemokines, growth factors, and metabolites. Simultaneously, they dynamically reprogram their metabolism according to environmental energy demands such as hypoxia and neo-vascularization. Such metabolic reprogramming can determine fates and functions of tumor cells as well as immune cells. Ultimately, glioma cells in the TME transform immune cells to suppress anti-tumor immune cells such as T, natural killer (NK) cells, and dendritic cells (DC), and evade immune surveillance, and even to promote (...)

Development of novel methods that monitor necroptosis and the release of DAMPs at the single cell resolution

Hiroyasu Nakano1,2, Shin Murai1, Yoshifumi Yamaguchi3, Yoshitaka Shirasaki4,5, Osamu Nakabayashi1 and Soh Yamazaki1

HOW DOES SMART SENSE THE EXECUTION OF NECROPTOSIS? Various types of cells undergo necroptosis following stimulation with death ligands including tumor necrosis factor, Fas ligand, and TRAIL, or polyI:C, and

R-loops: formation, function, and relevance to cell stress

David F Allison1,2 and Gang Greg Wang1,2

INTRODUCTION A variety of topological, structural and hybridization events occur during DNA replication and gene transcription. Unwinding of the DNA double helix provides access for polymerase to a template strand,

P4HA1 is a new regulator of the HIF-1 pathway in breast cancer

Ren Xu1,2

Prolyl hydroxylation is a very common posttranslational protein modification. About 4% amino acid residues in animal proteins are hydroxyproline, and most of hydroxyproline is within collagen. Regulation of protein stability

Control of nucleolar stress and translational reprogramming by lncRNAs

Yvessa Verheyden1, Lucas Goedert1,2 and Eleonora Leucci1

INTRODUCTION Unfavourable environmental conditions trigger cellular responses that help minimize and/or repair the damage experienced by the cell. During stress responses, most of the biosynthetic processes of the cell are

Serum- and glucocorticoid-inducible kinase 1 and the response to cell stress

Florian Lang1, Christos Stournaras2, Nefeli Zacharopoulou2, Jakob Voelkl3,4, Ioana Alesutan3,4,5

INTRODUCTION The ubiquitously expressed [1][2][3][4] serum- and glucocorticoid-inducible kinase 1 (SGK1) has originally been cloned as a gene up-regulated by serum and glucocorticoids in rat mammary tumor cells [1][5]. The

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LTX-315 – a promising novel antitumor peptide and immunotherapeutic agent

Dagmar Zweytick1,2

Host defense in mammals, as provided by the innate immune system, comprises proteins such as lactoferrin (LF), a multifunctional iron-binding glycoprotein originally discovered in bovine milk. LF is further pepsin-cleaved

Anti-regulatory T cells are natural regulatory effector T cells

Niels Ødum 1

It is well established that the immune system uses regulatory immune-suppressive cells to inhibit and terminate immune reactions and maintain immune balance. In the last decade, Andersen and colleagues have

The targeting of tumor-associated macrophages by vaccination

Mads Hald Andersen1,2,3

Immune suppressive myeloid cells include a heterogenous population of cells that include tumor-associated macrophages (TAMs). TAMs are major players in inducing the immunosuppressive microenvironment associated with many tumors. These lesions

Mitochondrial stress delays tumorigenesis in a Li-Fraumeni syndrome mouse model

Matthew P. Donnelly1, Jie Li1 and Paul M. Hwang1

As a prominent hub of metabolic activity, the mitochondrion can initiate retrograde signaling in response to bioenergetic stress that is important for various adaptive changes including cell cycle regulation [1][2].

Mitochondria organize the cellular proteostatic response and promote cellular senescence

Yanjun Li1, Lei Liu2, Yushan Zhu1 and Quan Chen1,2

Timely disposal and degradation of misfolded proteins and their aggregates is critical for cellular proteostasis and the well-being of a cell. During evolution, cells have acquired a sophisticated system to

Could de-stressing the brain be the solution for long-term weight loss?

Florian Seyfried1 and Mohammed K. Hankir2

INTRODUCTION One just needs to take a look at a typical vending machine (often found in hospitals) to appreciate what has happened to our food and drink. The relatively sudden